AU683447B2

AU683447B2 - Medicament for treating or preventing cerebrovascular diseases

Info

Publication number: AU683447B2
Application number: AU60455/94A
Authority: AU
Inventors: Kiyotaka Katsuta; Hajime Nakanishi; Hiroyuki Takamatsu; Yoshiko Ueda; Keizo Yoshida
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1993-03-08
Filing date: 1994-02-16
Publication date: 1997-11-13
Anticipated expiration: 2014-02-16
Also published as: CA2157671A1; EP0688216A1; AU6045594A; CN1118990A; KR960700711A; HU9402578D0; US5866598A; TW305760B; WO1994020102A2; HUT68293A; US5698561A; WO1994020102A3; JPH08507514A; US5607938A

Description

1

DESCRIPTION

NEW USE Technical Field The present invention relates to a new use of a compound having 5-HT antagonism.

More particularly, the present invention relates to a new use of a compound having 5-HT antagonism (hereinafter referred to as "5-HT antagonist") such as 5-HT 1 antagonism, 5-HT 2 antagonism and 5-HT 3 antagonism, especially 5-HT 3 antagonism for treating or preventing *cerebrovascular diseases.

Disclosure of the Invention The present invention provides a method for the treatment or prevention of cerebral infarction which need thereof comprises aministering to a mairmal a 5-HT antagonist.

eA It is known that 5-HT antagonists are of use for treating or preventing central nervous system (CNS) aisorders such as psychosis schizophrenia, mania, etc.), anxiety, and depression; pains or aches such as headaches migraine, cluster headaches, vascular headaches, etc.), and neuralgia trigeminal neuralgia, etc.); gastrointestinal disorders such as symptoms of gastrointestinal dysfunction such as occur with, for example, dyspepsia, pectic ulcer, reflux oesophagitis and flatulence, and irritable bowel syndrome (IBS); nausea or vomiting, each of which may be associated with cancer therapy; motion sickness; and the like.

C e 2 The inventors of the present invention extensively investigated various effects of the 5-HT antagonists, and during such investigations, it has been found that the antagonists are further of use for treating or preventing cerehrovascular diseases. This finding is really new and is not expectable at all for a person skilled in this field.

The 5-HT antagonist used in the present invention can be represented by the following general formulae

ORR

0 R 4 ,2 N R 3 I

R

*ooe I o** 4 a *po f o* o« o *o a WO 94/20102 PCT/JP94/00249 3 wherein R 1 is hydrogen, lower alkyl, lower alkenyl or N,N-di(lower)alkylaminomethyl,

R

2 is hydrogen, lower alkyl or halogen,

R

3 is imidazolyl or pyridyl, each of which may have suitable substituent(s), and R is hydrogen, lower alkyl, lower alkenyl or hydroxy(lower)alkyl and

R

5 is hydrogen, hydroxy or acyloxy, or 4 5 R and R are linked together to form an additional bond, or a pharmaceutically acceptable salt thereof,

OR

4

R

1 wherein R, R, R 3

R

4 and R 5 are each as defined above, or a pharmaceutically acceptable salt thereof, and Si A-R 9 (ii) N (III) R6 R 7 R R wherein R 7 and R 8 are each hydrogen, lower alkyl, lower alkenyl, aryl or ar(lower)alkyl, R is imidazolyl which may have suitable substituent(s) or pyridyl, WO 94/20102 PCT/JP94/00249 4 A is lower alkylene, and is single bond or double bond, or a pharmaceutically acceptable salt thereof.

In the compounds of the formulae (II) and (III), a suitable pharmaceutically acceptable salt of these compounds includes conventional one such as acid addition salt with an organic or inorganic acid (e.g.

hydrochloride, sulfate, formate, acetate, etc.), or a salt with a base such as alkali metal salt sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g.

calcium salt, etc.), organic basic salt (e.g.

cyclohexylamine salt, etc.), and the like.

The most preferred embodiment of the 5-HT antagonist used in the present invention is as follows.

8,9-Dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[l,2-a)indol-6(7H)-one or its hydrochloride salt; 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-iHimidazol-l-yl)methyl]-4H-carbazol-4-one or its hydrochloride and/or its hydrate; and 3,4-Dihydro-5-methyl-2-1l-(5-methyl-1H-imidazol-4yl)ethyl]pyrimido[l,6-alindol-1(2H)-one or its hydrochloride.

The compounds of the general formulae (II) and (III), and the specific compounds mentioned above are known compounds, and the methods for preparation thereof are described, for example, in the following publications, or they can be prepared by a conventional method.

WO 94/20102 PCT/JP94/00249 5 European Patent Publication 0361317A European Patent Publication 0191562A European Patent Publication 0420086A The suitable examples and illustrations of the various definitions used in the compounds of the formulae (II) and (III) are explained in detail in the following.

The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 4 carbon atoms, and the like, in which the most preferred one is methyl, ethyl or propyl.

Suitable "lower alkenyl" may include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is allyl.

Suitable "hydroxy(lower)alkyl" is lower alkyl as mentioned above which is substituted by hydroxy and may include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like, in which the most preferred one is hydroxymethyl.

Suitable "halogen" means fluoro, chloro, bromo and iodo, in which the most preferred one is chloro.

Suitable "imidazolyl" means 1H-imidazol-l-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl and Suitable "pyridyl" means 2-pyridyl, 3-pyridyl and 4-pyridyl.

Suitable substituent in the terms "imidazolyl or pyridyl, each of which may have suitable substituent(s)" WO 94/20102 PCT/JP94/00249 6 is conventional one used in a pharmaceutical field and may include lower alkyl as mentioned above, imino-protective group as mentioned below, and the like.

Suitable aiyl moiety in the term "acyloxy" may include conventional one derived, for example, from carboxylic, carbonic, sulfonic and carbamic acids, and the preferable example thereof is lower alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkanesulfonyl mesyl, ethanesulfonyl, propanesulfonyl, etc.), and the like, in which the mct preferred one is acetyl.

These acyl group may be substituted with suitable substituent(s) such as halogen chlorine, bromine, iodine, fluorine).

Suitable "imino-protective group" may include conventional one, and the preferable example thereof is ar(lower)alkyl such as mono-(or di- or tri-)phenyl(lower)alkyl benzyl, benzhydryl, trityl, etc.), acyl such as N,N-di(lower)alkylsulfamoyl (e.g.

N,N-dimethylsulfamoyl, etc.), lower alkanesulfonyl (e.g.

mesyl, etc.), arenesulfonyl tosyl, etc.), and the like, in which the most preferred one is trityl, benzyl or N,N-dimethylsulfamoyl.

Suitable "NN-di(lower)alkylaminomethyl" may include NN-dimethylaminomethyl, and the like.

Suitable "aryl" may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like, in which the preferred one is C 6

-C

10 aryl and the most preferred one is phenyl.

Suitable "ar(lower)alkyl" may include mono-(or di- or tri-)phenyl(lower)alkyl such as trityl, benzhydryl, benzyl, phenethyl, and the like, in whi:h the preferred WO 94/20102 PCT/IP94/00249 one is C 6

C

10 ar(C I- C alkyl and the most preferred one is benzyl.

Suitable "lower alkylene" may include straight or branched one, having I to 6 carbon atom(s), such as methylene, methylmethylene, ethylene, trimethyl ene, propylene, tetrarnethylene, and the like, in which the most preferr'ed one is methylmethylene.

Particularly, the preferred embodiments of R, R 2 R 3 R 4 R 5

R

6 ,r R 7 ,e R 8 R 9 A and are as follows.

R 1is hydrogen; lower alkyl such as methyl, ethyl, pr',pyl, etc.; lower alkeny. such as aJllyl, etc.; or N,N-di (lower) alkylaminomethyl such as N,N-dimetlhylaininomethyl, etc.; R2is hydrogen; lower alkyl such as methyl, etc.; or halogen such as chioro; R 3is iN-imidazolyl which may have one or more, preferably one to three substituent(s) selected from lower alkyl and imino-protective group such as 2-lower alkyl-lH-imidazol-1-yl 2-methyl-1H-imidazolimidazol-2-yl (eg. l-trityl-lH-imidazol-2-yl, etc.) 1-ar( lower) alkyl-5-lower alkyl-11{-imidazol-4-yl 5-methyl--trityl-1H-imidazol-4-yl, l-benzyl-5-methyl-lH-imidazol-4-yl, etc.), alkyl-1H-imidazol-4-yl 5-methyl-1Himidazol-4-yl, etc.), 1-ar(lower)alkyl-1H-imidazol- 4-yl 1-trityl-1I-imidazol-4-yl, etc.), IH-imidazol-4-ylf 2-lower alkyl-5-lower alkyl-1flimidazol-4-yl 2, 5-dimethyl,.1H-imidazol-4-yl, etc.), I1-ar (lower) fd.kyl- 2-lower alkyl-iN-imidazol- 2-lower alkyl-1H-imidazol-4-yl 2-methyl-ill- WO 94/20102 WO 9420102PCT/JP94/00249 8imidazol-4-yl, etc.), 1-lower alkyl-!H-imidazol-4-yl 1-methyl-1H-imidazol-4-yl, etc.), 1-lower alkyl-1H-imidazol-4-yl (e.g.

l,5-dimethyl-1H-imidazol-4-yl, etc.) and 1-di (lower) alkylaminosulfonyl-5-lower alkyl-1Himidazol-4-yl l-dimethylark'inosulfonyl- 5-methyl-lH-imidazol-4-yl, etc.), 1-lower alkyl-2.Hl-methyl--lH-imidazol-5-yl, etc.) and 1-lower alkyl-4-lower 1, 4-dimethy' 1H-imidazol-5-yl, etc.); pyridyl which may have lower alkyl. such as 3-pyridyl which may have suitable substituent(s) such as 3-pyridyl and 2-lower alkyl-3-pyridyl (e.g.

2-methyl-3-pyridyl, etc.); R 4 is hydrogen; lower alkyl such as methyl, ethyl, propyl, etc.; lower alkenyl such as allyl, etc.; or hydroxy(lower)alkyl such as hydroxymethyl, etc.; and Ris hydrogen; hydroxy; or acyloxy such as lower alkanoyloxy acei+,oxy, etc.), and the like; or Rand R5are linked together to form an additional bond; Ris hydrogen; lower al1~yl methyl, ethyl, isopropyl, etc.); lower alkenyl ally., aryl phenylt or ar(lower)alkyl such as mono- or di- or triphenyl%'1c~wer)alkyl benzyl, etc.); 11is hydrogen; or lower alkyl methyl, etc.); A8is hydrogen; r lower alkyl methyl, etc.);- Sis, imidazolyl which mnay have one to three substituent(s) selected from the group consisting of lower alkyl and imino-protective groupt for example, WO 94/20102 PCT/JI'94/00249 9 1H-imidazol-4-yl, 5-lower alkyl-1H-imidazol-4-yl 5-methyl-lH-imidazol-4-yl, 5-ethyl-IH-imidazol-4-yl, etc. alkyl-lH-imidazol-4-yl such as 1- mono- or di- or alkyl-lH-imidazol-4-yl (e.g.

l-trityl-5-methyl-lH-imidazol-4-yl, l-trityl-5-ethyl-1H-imidazol-4-yl, etc.), l-ar(lower)alkyl-1H-imidazol-4-yl such as 1- mono- or di- or triphenyl(lower)alkyl-H-imidazol-4-yl (e.g.

1-trityl-lH-imidazol-4-yl, etc.), 1-lower alkyl-H-imidazol-4-yl (e.g.

1-methyl-5-methyl-1H-imidazol-4-yl, etc.); pyr iyl 4-pyridyl, etc.); A is lower alkylene methylene, methylmethylene, ethylmethylene, etc.); and is single bond or double bond.

For therapeutic or preventive administration, the agent of the present invention are used in the form of conventional pharmaceutical preparation which contains the antagonist, as an active Ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration, The pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like.

If needed, there may be included in the above preparation auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, WO 94/20102 PCT/JP94/00249 10 talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like, While the dosage of the 5-HT antagonist may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the 5-HT antagonist to be applied, and the like. In general, amounts between 0.01 mg and about 500 mg or even more per day nay be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, mg, 100 mg, 200 mg, or 300 mg of the 5-HT antagonist may be used in the body.

In order to show the uefulness of the present inventions, the following examples are given.

Test Method The experiment was carried out using male Sprague Dawley rats (272-345 The animals were anesthetized with 2% halothane in a mixture of 70% nitrous oxide and a balance of oxygen delivered through a close fitting face mask. The animals were placed in the lateral position, and a 2 cm skin incision was made at the midpoint between the left orbit and the external auditory canal without removing the zygomatic arch. The temporal muscle was divided midway vertically and reflected forward and downward with a retractor. The inferotemporal fossa was exposed under a surgical microscope, and a small craniectomy was made using a dental drill. The proximal portion of the middle cerebral artery was permanently electrocoagulated with bipolar forceps and was cut to ensure the completeness of the vascular occlusion. The skin was sutured, and the animals were returned to their cages.

Twenty four hours after ischemia, the animals were aneshetized with thiopental-Na (50 mg/kg, and then I~R~ll(~f*~LIAIIY"-~~"- PCT/JIT4/00249 WO 94/20102 1 sacrificed by intracardiac perfusion with 200 ml of heparinized saline. The brain was.cut into 6 coronal slices (2 mm thick), the brain slices were stained with 2% triphenyltetrazolium chloride in saline at 37 0

C.

The areas of ischemic damage were delineated at 6 preselected coronal levels from anterior 3.75 mm to arterior 13.5 mm, and the extent of ischemic damage were determined from these photographs using a digitizer. The ischemic damage was expressed as of total infarction areas. The drugs were injected intravenously via tail vein immediately after surgery.

The statistical analyses of data were carried out using Dunnett's test.

Test Compounds (+)-8,9-Dihydro-10-methyl-7-[(5-methyl-lH-imidazol-4yl)methyl]pyridol1,2-alindol-6(7H)-one hydrochloride [hereinafter referred to as Compound A] 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-lH-imidazoll-yl)methyl -4H-carbazol-4-one hydrochloride dihydrate [hereinafter referred to as Compound B] (+)-3,4-Dihydro-5-methyl-2-[l-(5-methyl-lH-imidazol- 4-yl)ethyl)pyrimido[l,6-a]indol-1(2H)-one hydrochloride [hereinafter referred to as Compound C1 Test Result Table. Effects of 5-HT antagonists on ischemic damage by focal brain ischemLa 12 do.ge of infarction area drug (mg/kg, n(Mean control C (saline) 8 21.74 ±1.49 Compound A 0.001 8 19.02 ±1.37 0.01 8 18.51 ±0.89 0.1 8 16.97 ±1.12 control C' (saline) 8 16.65 i 0.82 Compound B 1.0 8 14.78 t 1.39 I0.0 8 11.40 0.48 control C (saline) 8 18.65 0.76 Compound C 0101 7 16.09 1 1.12 0.1 8 14.12 i 1.46* 7 13.13 1.13* *6 C@

C

*0 C. C SC

C

CCC.

C

'CCC

S.C.

C

C.

C

.C C <0.05 <0.01 vs control C.o *se

S.

so.

As evident from the Test Results, the antagonists showed decrease of cerebral infarction area, and therefore are of much use for treating and preventing cerebrovascular diseases.

Z

1z 13- The ability for compounds used in the present invention to penetrate the blood brain barrier has been demonstrated by the following example.

The experiment was carried out by using a representative compound, 4 C-labeled (+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indole-6(7H)one hydrochloride 4 C]-compound A).

The chemical formula of 4 C]-compounu A is shown as follows.

1H3 Ht I HCI

H

3 C CH 2

CI

0 Test method 15 '["C]-compound A (Img/kg) was administered to male rats by injecting intravenously.

minutes after the administration, the concentration of radioactivity in blood plasma, brain and liver was measured by autoradiography.

Test result 20 organ concentration(I g/ml) blood plasma 0.32 brain 1.71 liver 1.78

S

4S**

S

*55e

S

S *0

S

a.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

i; C s~

V

C1I I

Claims

14- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS; 1. A method for treating or preventing cerebral ne A Vre. infarction which comprises administering to a mammal Aa compound of the formula: 0R4 P 2 N RI3 wherein R Iis hydrogen, lower alkyl, lower alkenyl or 2 N,N-di (lower) alkylaminomethyl, R 2is hydrogen, loser alkyl or halogen, R. R 3 is imidazolyl or pyridyl, each of which may have suitable substituent(s), and 4 R~ is hydrogen, lower alkyl, lower alkenyl or hydroxy( lower) alkyl and R 5 is hydrogen, hydroxy or acyloxy, or 4 R~ and R. are linked together to form an :additional bond, or a pharmaceutically acceptable salt thereof, *00*R RO R wherein R I, R 2 P 3 R4 and R 5are each as defined above, or a pharmaceutically acceptable salt thereof, or R 6 R7 6, 7 8 cl wherein R ,R and R. are each hydrogen, lower alkyl lower alkenyl, aryl or ar(lower)alkyl, R 9is imidazolyl which may have suitable substituent(s) or pyridyl, A is lower alkylene, and is single bond or double bond or a pharmaceutically acceptable salt thereof. 2. A method of claim 1 which comprises administering the compound MI defined in Claim 1 to a mammal.

43. A method of claim 2, wherein the compound MI is d:Lhydrc-lO-methyl-7- [(5-methyl-lH-imidazol-4- yl)methyll pyridofi, 2-a] indol-G (7H) -one hydrochloride. .4..tisSCN dyo ANAY19 B DAVtIS CON dAVfJAURY19 Patent Attorneys for the applicant(s) 4(-x I INTERNATIONAL. SEARCH REPOC)RT la l ,l applicaon No PCT/JP 94/00249 A. CLASSIFICATION OF SUBJIEC MA'IT'RF IPC 5 A61K31/415 A61K31/44 A61K31/445 A61K31/505 According to International Patent (lassification (IPC or to both national classification and IPC B. FIELDS SEARChIED Minimum documentation searched (classification system followed by classification symbols) IPC 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practcal, search terms used) C. DOCUMliNTS CONSIIIORED TO 1RI RELEVANT Category Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No, X EP,A,O 451 538 (FUJISAWA PHARMACEUTICAL 1,2,5,6 CO., LTD.) 16 October 1991 see page 14, line 23 see page 14, line 31-45 X EP,A,O 275 668 (GLAXO GROUP LIMITED) 27 1,2 July 1988 see page 2, line 37 X EP,A,O 357 415 (GLAXO GROUP LIMITED) 7 1,2 March 1990 see page 3, line X EP,A,O 279 990 (GLAXO GROUP LIMITED) 31 1,2 August 1988 see page 2, line 29 Further documents are listed in the continuation of box C. I Patent fanmly members are listed in annex. Special categories of cited documents: 'T later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not ted to understand the principle or theory underlying the considered to be of particular relevance invention earlier document hut published on or after the international X' document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority clam(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot he considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published pnor to the International filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completon of the international search Date of mailing of the international sarch report May 1994 I 6 0 _94t Name and mailing address of tl-e ISA Authorized officer lEuropean Patent Office, P.U. 5818 PatenUaan 2 NI, 2280 HV Rilwilk Tel. 310) 340.2040, Tx. 31 651 epo n, THEUNS H Fax: 31.70) 340.3016 Form PCT ISA..O (ieccnd heet) (July 1992)J page 1 of 2 I NJTCi RNAT1 1 ONA 1. S flA k(1 I itn m0 wr r iitct )nMI ApPlIC ~tiovt No PCT/JP 94/00249 C.(Continuation) OOCUME3NTS CONSID1ERVD TO Ur~ Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP,A,O 492 020 (MERRELL DOW 1,2 PHARMACEUTICALS INC.) 1 July 1992 see page 7, line 22 line 23 xEP,A,0 494 002 (MERRELL DOW 1,2 PHARMACEUTICALS INC.) 8 July 1992 see page 6, line 22 EP,A,0 361 317 (FUJISAWA Co. LTD. 4 April1 1990 cited in the application see claim 9 PHARMACEUTI CAL EP,A,0 420 086 (FUJISAWA PHARMACEUTICAL CO., LTD.) 3 April1 1991 cited in the application see claim 8 EP,A,0 191 562 (GLAXO GROUP LIMITED) August 1986 cited in the application Form PCT ISA.210 (Iwntnustii Of itend ahett) (July 1992) page 2 of 2 i INTERNATIONAL SEARCH REPORT ernAtional application No. PCT/JP 94/00249 L- Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. X Claims Nos,: because they relate to subject matter not required to be searched by this Authority, namely. Although claims 3-4 and 7-8 are directed to a method of treatment of the human/animal body, the search was based on the alleged effects of the com- pounds/compositions as expressed in claim 1. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6,4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. The use of compounds of formula for the manufacture of a medicament for treating or preventing cerebrovascular diseases; pharrmceutical compositions comprising a compound of formula (Claims 1,3,5 and 7, each partially, and claims 2,4,6 and This subject was searched. For further information please see annex. 1. D As all required additional search fe.s were timely paid by the applicant, this international search report covers all searchable claims. 2. O As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee, 3. As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: 1,3,5,7, each partially, and 2,4,6 and 8. Remark on Protest R The additional r; trch fees were accompanied by the applicant's protest F-I No protest accompanied the payment of additional search fees, Form PCT/ISA/210 (continuation of first sheet (July 1992) International Application No. PCT/JP 94/ 00249 FURTHER INFORMATION CONTINUED FROM PCTISAI CONTINUATION OF BOX II: 2. The use of compounds of formula (II) for the manufacture of a medicament for treating or preventing cerebrovascular diseases; pharmaceutical compo- sitions comprising a compound of formula (II) (Claims 1,3,5 and 7, each partially); This subject was not searched. 3. The use of compounds of formula (III) for the manufacture of a medicament for treating or preventing cerebrovascular diseases; pharmaceutical compo- sitions comprising a compound of formula (III) (Claims 1,3,5 and 7, each pa partially); This subject was also searched. INTERINATPIONAL~ SliAR("I REWORT Intcli nal Application No information on pawen( 'smily mcmheri PCT/JP 94/00249 Patent. document Publication Patent family Pubicatioii cited In search report date member(s) L date EP-A-0451538 16-10-91 US-A- 5173493 -12-92 JP-A- 4270280 25-09-92 US-A- 5290785 01-03-94 EP-A-0275668 27-07-88 AU-B- 618520 02-01-92 AU-A- 8261487 23-06-88 OE-A- 3782028 05-11-92 ES-T- 2052585 16-07-94 ~JP-A- 63253083 20-10-88 US-A- 4845115 04-07-89 EP-'A-0357415 07-03-90 AU-B- 627769 03-09-92 AU-A- 4096789 08-03-90 CA-A- 1330536 05-07-94 JP-A- 2180824 13-07-90 US-Ak 5229407 20-07-93 EP-A-0279990 31-08-88 EP-A- 0551963 21-07-93 EP-A- 0559297 08-09-93 JP-A- 63277623 15-11-88 US-A- 4985437 15-01-91 US-A- 5190954 02-03-93 US-A- 5200414 06-04-93 US-A- 54A4909 14-09-93 EP-A-0492020 01-07-92 AU-B- 652009 11-08-94 AU-A- 8C'1891 25-06-92 EP-A- 0494002 08-07-92 LIP-A- 4334381 20-11-92 EP-A-0494002 08-07-92 EP-A- 0492020 01-07-92 AU-B- 652009 11-08-94 AU-A- 8981891 25-06-92 JP-A- 4334381 20-11-92 EP-A-0361317 04-04-90 AU-B- 627221 20-08-92 AU-A- 4140689 05-04-90 Fl-B- 92200 30-06-94 JP-A- 2117675 02-05-90 JP-B- 5004392 19-_01-93 Form PCT ISA210 1pattnt family arintXl (July 1991) page 1 of 2 IN'TVRNAIONAI. SIARCI I RIPQP.T It montinon p~ent ;a4mily in~crr PCT/,JP 94/00249 Patent document Publication Patent famnily Publication~ cited in search report date member(s) I date EP-A-036 1317 US-A- 5173493 22-12-92 US-A- 5290785 01-03-94 EP-A-04200865 03-04-91 JP-A- 3141?6 17-06-91 US-A- 5180728 19-01-93 US-A- 5256780 26-10-93 EP-A-01', 562 20-08-86 AU-B- 583343 27-04-89 AU-A- 5261486 31-07-86 JP-A- 61210083 18-09-86 US-A- 4695578 22-09-87 Form PCT'ISA210 (patent family aaeeax) (Jly 19021 page 2 of 2